Processes and intermediates useful to make antifolates

Abstract

The present application relates to a series of novel sulfonic acid metal cation salts of the formula ##STR1## which are useful intermediates to prepare antifolate 5-substituted pyrrolo[2,3-d]pyrimidines. The present invention also relates to a novel process for preparing the sulfonic acid metal cation salts and to a novel process for preparing aldehydes of the formula ##STR2## from the corresponding sulfonic acid metal cation salts.

We claim: 
     
       1. A compound of formula IV: ##STR15## wherein: M is a metal cation; n is 1 or 2;   R 2  is NHCH(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  ;   R 3  is independently at each occurrence a carboxy protecting group; and   X is a bond or C 1  -C 4  alk-diyl.   
     
     
       2. The compound according to claim 1 wherein X is a bond, --CH 2  --, or --CH 2  CH 2  -- and R 2  is NHC*H(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  where the configuration about the carbon atom designated * is L. 
     
     
       3. The compound according to claim 2 wherein X is --CH 2  --. 
     
     
       4. The compound according to claim 1 wherein M is an alkali metal cation and n is 1 and R 2  is NHC*H(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  where the configuration about the carbon atom designated * is L. 
     
     
       5. The compound according to claim 4 wherein the alkali metal is sodium. 
     
     
       6. The compound according to claim 1 wherein M is sodium, n is 1, X is --CH 2  --, and R 2  is NHC*H(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  where the configuration about the carbon atom designated * is L. 
     
     
       7. A process for preparing a compound of formula IV: ##STR16## wherein: M is a metal cation; n is 1 or 2;   R 2  is NHCH(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  ;   R 3  is independently at each occurrence a carboxy protecting group;   X is a bond or C 1  -C 4  alk-diyl; comprising:     reacting a compound of formula III: ##STR17##  wherein: R 2  and X are as defined above for formula IV; with a compound of the formula M(HSO 3   - ) n  :   wherein:     M is defined above for formula IV; and   n is 1 or 2; in a solvent.     
     
     
       8. The process according to claim 7 wherein the compound of formula III is a compound wherein X is a bond, --CH 2  --, or --CH 2  CH 2  -- and R 2  is NHC*H(CO 2  R 3 )CH 2  CH 2  CO 2  R 3  or OR 3  where the configuration about the carbon atom designated * is L. 
     
     
       9. The process according to claim 8 wherein X is --CH 2  --. 
     
     
       10. The process according to claim 9 wherein the compound of the formula M(HSO 3   - ) n  is a compound wherein M is an alkali metal cation and n is 1 and the reaction is performed at a temperature between 35° C. and 50° C. 
     
     
       11. The process according to claim 10 wherein the alkali metal is sodium. 
     
     
       12. The process according to claim 7 wherein the solvent is a mixture of ethyl acetate, 3A-ethanol, and water. 
     
     
       13. The process according to claim 7 further comprising: reacting a compound of formula I: ##STR18##  wherein: R 4  is hydrogen or C 1  -C 4  alkyl; and X' is a bond or C 1  -C 4  aik-diyl; with the proviso that if X' is not a bond, then the carbon alpha to the alcohol must be a --CH 2  -- moiety;       with a compound of formula II: ##STR19##  wherein: R 2  is defined above for formula IV; and Lg is a leaving group;     in a solvent, in the presence of a palladium catalyst and a phase transfer catalyst, and optionally in the presence of a metal cation chloride, to afford a compound of formula III.   
     
     
       14. The compound according to claim 1 which is: ##STR20## 
     
     
       15. The compound according to claim 1 which is 1-hydroxy-4-(4-carbomethoxyphenyl) butanesulfonic acid sodium salt.